CDKL5 encodes a serine/threonine kinase critical for normal brain development and function. The protein mediates phosphorylation of MECP2 and may regulate ciliogenesis. CDKL5 is essential for axon outgrowth, dendritic morphogenesis, and synapse formation, maturation, and maintenance 1. The kinase activity includes phosphorylation of EB2, a bona fide CDKL5 substrate 1. Pathogenic variants in CDKL5 cause CDKL5 deficiency disorder (CDD), a severe developmental and epileptic encephalopathy characterized by early-onset seizures within the first 2 months of life that are typically refractory to conventional antiseizure medications 2. Development is severely impaired in CDD patients, with only a quarter of girls and a smaller proportion of boys achieving independent walking 2. The disorder presents with hypotonia and failure to reach cognitive and motor developmental milestones 1. Common comorbidities include gastrointestinal, sleep, and musculoskeletal problems, with cerebral visual impairment appearing more prevalent in CDD than other developmental epileptic encephalopathies 2. Gene therapy approaches using adeno-associated virus vectors to deliver CDKL5 to the brain show promise in preclinical studies, with functional improvements observed when achieving broad neuronal transduction 1.